scholarly journals L1 TGF-beta blocks type I IFN release and tumor rejection in spontaneous mammary tumors

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A1.1-A1
Author(s):  
N Bercovici ◽  
MV Guérin ◽  
F Regnier ◽  
JM Weiss ◽  
V Feuillet ◽  
...  
Keyword(s):  
Immune Cells ◽  
Tumor Regression ◽  
Mammary Tumors ◽  
Tumor Rejection ◽  
Type I ◽  
Cancer Therapies ◽  
Type I Ifn ◽  
Spontaneous Tumors ◽  
Primary Tumors ◽  
Tlr4 Agonist

BackgroundActivation of the STimulator of INterferon Genes (STING) by DMXAA (5,6-dimethylxanthenone-4-acetic acid) can induce a strong production of IFNα/β and the rejection of transplanted primary tumors. However, the efficacy of such therapeutic approach for the treatment of spontaneous tumors had still to be evaluated.Material and MethodsWe have tested whether the injection of DMXAA or other STING agonists and TLR4 agonist, could lead to the regression of spontaneous MMTV-PyMT mammary tumors. We also characterized, in time and space, the early signaling events triggered downstream STING and the distribution of infiltrating immune cells in the tumor microenvironment by fluorescence imaging.ResultsWe show that spontaneous MMTV-PyMT mammary tumors are resistant to immunotherapeutic intervention. We demonstrate that TGFβ, abundant in spontaneous tumors, is a key molecule limiting this IFN-induced-tumor regression by DMXAA. Mechanistically, we found that TGFβ blocks the phosphorylation of IRF3 and the ensuing IFNα/β production by tumor infiltrating macrophages. Finally, blocking TGFβ restores the production of IFNα by activated MHCII+ tumor-associated macrophages, and enables tumor regression induced by STING activation.ConclusionsBased on these findings, we propose that the efficacy of many cancer therapies, which are type I IFN-dependent, should be greatly improved by combination with TGFβ blockade.Disclosure InformationN. Bercovici: None. M.V. Guérin: None. F. Regnier: None. J.M. Weiss: None. V. Feuillet: None. L. Vimeux: None. G. Altan-Bonnet: None. E. Donnadieu: None. A. Trautmann: None.

scholarly journals TGFβ blocks IFNα/β release and tumor rejection in spontaneous mammary tumors

2018 ◽  
Author(s):  
Marion V. Guerin ◽  
Fabienne Regnier ◽  
Vincent Feuillet ◽  
Lene Vimeux ◽  
Julia M. Weiss ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Mammary Tumors ◽  
Tumor Rejection ◽  
Type I Interferons ◽  
Type I ◽  
Cancer Therapies ◽  
Type I Ifn ◽  
Spontaneous Tumors ◽  
Tumor Associated Macrophages ◽  
Primary Tumors

SummaryType I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA can induce a strong production of IFNα/β and the rejection of transplanted primary tumors. In the present study, we addressed whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFNα/β production. Mechanistically, we identified TGFβ abundant in spontaneous tumors, as a key molecule limiting this IFN-induced-tumor regression by DMXAA. Finally, blocking TGFβ restores the production of IFNα by activated MHCII+tumor-associated macrophages, and enables tumor regression induced by STING activation. On the basis of these findings, we propose that type I IFN-dependent cancer therapies could be greatly improved by combinations including the blockade of TGFβ.

scholarly journals TGFβ blocks IFNα/β release and tumor rejection in spontaneous mammary tumors

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Marion V. Guerin ◽  
Fabienne Regnier ◽  
Vincent Feuillet ◽  
Lene Vimeux ◽  
Julia M. Weiss ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Tumor Regression ◽  
Mammary Tumors ◽  
Tumor Rejection ◽  
Type I Interferons ◽  
Type I ◽  
Cancer Therapies ◽  
Type I Ifn ◽  
Spontaneous Tumors ◽  
Primary Tumors

Abstract Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA (5,6-dimethylxanthenone-4-acetic acid) can induce strong production of IFNα/β and rejection of transplanted primary tumors. In the present study, we address whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFNα/β production. Mechanistically, we identify TGFβ, which is abundant in spontaneous tumors, as a key molecule limiting this IFN-induced tumor regression by DMXAA. Finally, blocking TGFβ restores the production of IFNα by activated MHCII+ tumor-associated macrophages, and enables tumor regression induced by STING activation. On the basis of these findings, we propose that type I IFN-dependent cancer therapies could be greatly improved by combinations including the blockade of TGFβ.

scholarly journals Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden

2017 ◽  
Vol 114 (51) ◽  
pp. E10981-E10990 ◽  
Author(s):  
Meredith L. Stone ◽  
Katherine B. Chiappinelli ◽  
Huili Li ◽  
Lauren M. Murphy ◽  
Meghan E. Travers ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Histone Deacetylase Inhibitors ◽  
Unmet Need ◽  
Tumor Burden ◽  
Epigenetic Therapy ◽  
Type I ◽  
Type I Ifn

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING

2017 ◽  
Vol 31 (7) ◽  
pp. 3107-3115 ◽  
Author(s):  
Christine Rueckert ◽  
Ulfert Rand ◽  
Urmi Roy ◽  
Bahram Kasmapour ◽  
Till Strowig ◽  
...  
Keyword(s):  
Immune Cells ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Cells ◽  
Type I Ifn ◽  
Cyclic Dinucleotides

scholarly journals Type I interferon is selectively required by dendritic cells for immune rejection of tumors

2011 ◽  
Vol 208 (10) ◽  
pp. 1989-2003 ◽  
Author(s):  
Mark S. Diamond ◽  
Michelle Kinder ◽  
Hirokazu Matsushita ◽  
Mona Mashayekhi ◽  
Gavin P. Dunn ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Type I Interferon ◽  
Tumor Rejection ◽  
Type I ◽  
Type I Ifn ◽  
Cancer Immunoediting ◽  
Cross Presentation ◽  
Tumor Immunogenicity ◽  
Β Receptor ◽  
Macrophage Populations

Cancer immunoediting is the process whereby the immune system suppresses neoplastic growth and shapes tumor immunogenicity. We previously reported that type I interferon (IFN-α/β) plays a central role in this process and that hematopoietic cells represent critical targets of type I IFN’s actions. However, the specific cells affected by IFN-α/β and the functional processes that type I IFN induces remain undefined. Herein, we show that type I IFN is required to initiate the antitumor response and that its actions are temporally distinct from IFN-γ during cancer immunoediting. Using mixed bone marrow chimeric mice, we demonstrate that type I IFN sensitivity selectively within the innate immune compartment is essential for tumor-specific T cell priming and tumor elimination. We further show that mice lacking IFNAR1 (IFN-α/β receptor 1) in dendritic cells (DCs; Itgax-Cre+Ifnar1f/f mice) cannot reject highly immunogenic tumor cells and that CD8α+ DCs from these mice display defects in antigen cross-presentation to CD8+ T cells. In contrast, mice depleted of NK cells or mice that lack IFNAR1 in granulocytes and macrophage populations reject these tumors normally. Thus, DCs and specifically CD8α+ DCs are functionally relevant targets of endogenous type I IFN during lymphocyte-mediated tumor rejection.

scholarly journals Hypoxia regulates endogenous double-stranded RNA production via reduced mitochondrial DNA transcription

2020 ◽  
Author(s):  
Esther Arnaiz ◽  
Ana Miar ◽  
Antonio Gregorio Dias ◽  
Naveen Prasad ◽  
Ulrike Schulze ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Type I Interferon ◽  
Type I ◽  
Cancer Therapies ◽  
Common Phenomenon ◽  
Type I Ifn ◽  
Hallmarks Of Cancer ◽  
Mitochondrial Transcription ◽  
Double Stranded Rna ◽  
Local Immunosuppression

ABSTRACTHypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Hypoxia promotes local immunosuppression and downregulates type I interferon (IFN) expression and signalling, which contribute to the success of many cancer therapies. Double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activates the type I IFN pathway. We report the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer. We found a significant decrease in dsRNA production in different cell lines under hypoxia. This was HIF1α/2α-independent. mtdsRNA was responsible for induction of type I IFN and significantly decreased after hypoxia. Mitochondrially encoded gene expression was downregulated and mtdsRNA bound by the dsRNA-specific J2 antibody was decreased during hypoxia. These findings reaveal a mechanism of hypoxia-induced immunosuppression that could be targeted by hypoxia-activated therapies.

scholarly journals Recognition ofBorrelia burgdorferi, the Lyme Disease Spirochete, by TLR7 and TLR9 Induces a Type I IFN Response by Human Immune Cells

2009 ◽  
Vol 183 (8) ◽  
pp. 5279-5292 ◽  
Author(s):  
Mary M. Petzke ◽  
Andrew Brooks ◽  
Michelle A. Krupna ◽  
Dana Mordue ◽  
Ira Schwartz
Keyword(s):  
Lyme Disease ◽  
Immune Cells ◽  
Type I ◽  
Type I Ifn ◽  
Human Immune

scholarly journals Hypoxia Regulates Endogenous Double-Stranded RNA Production via Reduced Mitochondrial DNA Transcription

2021 ◽  
Vol 11 ◽  
Author(s):  
Esther Arnaiz ◽  
Ana Miar ◽  
Antonio Gregorio Dias Junior ◽  
Naveen Prasad ◽  
Ulrike Schulze ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Type I Interferon ◽  
Type I ◽  
Cancer Therapies ◽  
Common Phenomenon ◽  
Type I Ifn ◽  
Hallmarks Of Cancer ◽  
Mitochondrial Transcription ◽  
Double Stranded Rna ◽  
Local Immunosuppression

Hypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Hypoxia promotes local immunosuppression and downregulates type I interferon (IFN) expression and signalling, which contribute to the success of many cancer therapies. Double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activates the type I IFN pathway. We report the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer. We found a significant decrease in dsRNA production in different cell lines under hypoxia. This effect was HIF1α/2α-independent. mtdsRNA was responsible for induction of type I IFN and significantly decreased after hypoxia. Mitochondrially encoded gene expression was downregulated and mtdsRNA bound by the dsRNA-specific J2 antibody was decreased during hypoxia. These findings reveal a new mechanism of hypoxia-induced immunosuppression that could be targeted by hypoxia-activated therapies.

scholarly journals Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production

2021 ◽  
Vol 131 (1) ◽  
Author(s):  
Line S. Reinert ◽  
Ahmad S. Rashidi ◽  
Diana N. Tran ◽  
Georgios Katzilieris-Petras ◽  
Astrid K. Hvidt ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Immune Cells ◽  
Herpes Simplex Virus Type ◽  
Type I ◽  
Type I Ifn ◽  
Simplex Virus

scholarly journals Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection

2021 ◽  
Vol 17 (9) ◽  
pp. e1009878
Author(s):  
Martina Severa ◽  
Roberta A. Diotti ◽  
Marilena P. Etna ◽  
Fabiana Rizzo ◽  
Stefano Fiore ◽  
...  
Keyword(s):  
Viral Replication ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Lung Epithelial Cells ◽  
Interferon Response ◽  
Cell Surface Expression ◽  
Cell Phenotype ◽  
Type I ◽  
Type I Ifn

SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent but Neuropilin-1-dependent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients.

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